Previous studies have suggested that use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reduced risk of lung cancer, but the data are inconsistent and are limited particularly with respect to the effects of aspirin, separate from other NSAIDs.

The Iowa Women's Health Study is a prospective cohort of 41,836 Iowa women ages 55 to 69 years old at baseline in 1986. NSAID use was assessed in 1992. Over 10 years of follow-up, 403 incident cases of lung cancer were identified. The association of incident lung cancer with current use of aspirin or non-aspirin NSAIDs was analyzed after adjustment for lung cancer risk factors. Hazard ratios (HR) were estimated using multivariate COX proportional hazards regression.

There were 27,162 women in the analytic cohort. After controlling for age, education, alcohol intake, pack-years, smoking status, body mass index, and total fruit intake, the RR of women taking six or more aspirin weekly was 1.21 (95% confidence interval, 0.92-1.59). The HR was 1.23 for women taking six or more non-aspirin NSAIDs weekly (95% confidence interval, 0.92-1.65). There was no statistically significant trend by frequency of use for either aspirin (P(trend) = 0.22) or non-aspirin NSAIDs (P(trend) = 0.53). Analyses by histologic type and smoking status yielded similar null results. Information on dosage and duration of use were not available for this analysis.

These findings do not suggest that aspirin or other NSAIDs reduce risk of lung cancer in this cohort of postmenopausal women.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant, that has been linked with a variety of deleterious effects on human health, including increased cancer rates and reproductive anomalies. The detrimental effects of TCDD are mediated via the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of the carcinogen-activating enzymes cytochromes P-450 (CYP) 1A1, 1A2, and 1B1. In the present study, we examined the ability of synthetic derivatives of salicylic acid to affect TCDD-stimulated AhR-mediated signal transduction in human hepatoma HepG2 cells. Salicylamide (SAL), an analgesic drug, caused a potent and long-lasting inhibition of TCDD-induced CYP enzyme activity. Acetylsalicylic acid (aspirin) and the naturally occurring phytochemical salicylic acid had no effect on CYP activity. SAL inhibited the increase in CYP1A1, -1A2, and -1B1 mRNA levels that occurs on exposure to TCDD. TCDD-induced transcription of these genes was also inhibited by SAL, but not by aspirin or salicylic acid, as demonstrated by luciferase reporter assays. The transcription of the CYP1 family of genes is regulated by the interaction of TCDD-activated AhR with the xenobiotic-responsive element present in the promoter regions of these genes. As shown by electrophoretic mobility shift assay, SAL completely blocked the binding of TCDD-activated AhR to the xenobiotic responsive element. Also, SAL substantially blocked the binding of TCDD to the cytosolic AhR. These results demonstrate that SAL, a commonly used analgesic, is a potent inhibitor of AhR-mediated signal transduction, and may be an effective agent in the prevention of TCDD-associated disease.

Evidence of a protective role of aspirin on the risk of colorectal and other common cancers has been building up since the end of the 1980s. There are now more than 15 epidemiological (case-control and cohort) studies indicating that long-term use of aspirin is associated with a reduced risk of colorectal cancer. The overall relative risk (RR) estimate for regular aspirin users was 0.71 (95% confidence interval (CI) 0.66-0.77) from case-control studies, and 0.84 (95% CI 0.72-0.98) from cohort studies. A recent meta-analysis reported a RR of breast cancer for aspirin use of 0.70 (95% CI 0.61-0.81) in case-control studies, and of 0.79 (95% CI 0.59-1.06) in cohort studies. Furthermore, various epidemiological studies have suggested that aspirin use might have a favourable effect on ovarian cancer as well: the overall RR estimate was 0.82 (95% CI 0.69-0.99), although the evidence is too limited to permit firm conclusions. Data are more scanty, though in the same direction, for other neoplasms, including in particular stomach and oesophageal cancer.

Infection with the human immunodeficiency virus (HIV) invariably leads to the development of acquired immunodeficiency syndrome (AIDS) in most infected humans, yet does so rarely, if at all, in HIV-infected chimpanzees. The differences between the two species are not due to differences in cellular receptors or an inability of the chimpanzee to be infected, but rather to the lack of pan-immune activation in the infected primate. This results in reduced apoptotic death in CD4+ T-helper lymphocytes and a lower viral load. In humans the degree of chronic immune activation correlates with virus load and clinical outcome with high immune activation leading to high viral loads and the more rapid progression to AIDS and death. The type of immune perturbation seen in HIV-associated AIDS is similar to that of chronic graft-versus-host disease (GVHD) where reduced cell-mediated immune (CMI) responses occur early in the course of the disease and where humoral responses (HI) predominate. A reduced CMI response occurs in a number of chronic infectious diseases, including tuberculosis and leishmaniasis. More recently, it has become increasingly apparent that the CMI response is suppressed in virtually all malignant diseases, including melanoma and colorectal and prostate cancer. This raises the possibility that, as the malignant process develops, the cancer cells evolve to subvert the CMI response. Moreover, the reduced CMI response seen in colorectal cancer (CRC) patients is completely reversed following curative surgery strongly supporting the hypothesis that CRC can suppress the systemic immune response. Wound healing, ovulation, embryo implantation, and fetal growth are all associated with suppressed CMI and neovascularization (the formation of new blood vessels) or angiogenesis (the formation of new blood vessels from an existing vasculature). If unresolved, wound healing results in chronic inflammation, which can give rise to the phenomenon of "scar cancers." Indeed all the chronic inflammatory conditions known to be associated with the subsequent development of malignant disease, including chronic obstructive airway disease (COPD), ulcerative colitis (UC), and asbestosis, give rise to similar proangiogenic, suppressed CMI, and HI-predominant environments. In keeping with this CMI-associated cytokines such as interleukin (IL)-2 and interferon (IFN)-gamma tend to be antiangiogenic, whereas HI cytokines such as IL-6 tend to be proangiogenic. Furthermore, chronic immune activation leads to the synthesis and release of factors such as macrophage inflammatory protein (MIP)-1 that inhibit apoptosis through suppression of p53 activity. The "Golden Triangle" of suppressed CMI, angiogenesis, and reduced apoptosis would provide the ideal environment for the serial mutations to occur that are required for the development of malignant disease. If the observed association is relevant to carcinogenesis, then treatments aimed at reducing the components of these inflammatory conditions may be useful both in the setting of chemoprevention and the therapeutic management of established disease.

Several chronic infections known to be associated with malignancy have established oncogenic properties. However the existence of chronic inflammatory conditions that do not have an established infective cause and are associated with the development of tumours strongly suggests that the inflammatory process itself provides the prerequisite environment for the development of malignancy. This environment includes upregulation of mediators of the inflammatory response such as cyclo-oxygenase (COX)-2 leading to the production of inflammatory cytokines and prostaglandins which themselves may suppress cell mediated immune responses and promote angiogenesis. These factors may also impact on cell growth and survival signalling pathways resulting in induction of cell proliferation and inhibition of apoptosis. Furthermore, chronic inflammation may lead to the production of reactive oxygen species and metabolites such as malondialdehyde within the affected cells that may in turn induce DNA damage and mutations and, as a result, be carcinogenic. Here it is proposed that the conditions provided by a chronic inflammatory environment are so essential for the progression of the neoplastic process that therapeutic intervention aimed at inhibiting inflammation, reducing angiogenesis and stimulating cell mediated immune responses may have a major role in reducing the incidence of common cancers.

We carried out a nested case-control study to measure the rate ratio (RR) for invasive female breast cancer in relation to non-steroidal anti-inflammatory drug (NSAID) use. The source population consisted of the female beneficiaries of the Saskatchewan Prescription Drug Plan from 1981 to 1995 with no history of cancer since 1970. Four controls/case, matched on age and sampling time, were randomly selected. Dispensing rates during successive time periods characterized NSAID exposure. RRs associated with exposure during each period were adjusted for exposure during the others. Confounding by other determinants was studied in analyses adjusted with data obtained by interviewing samples of subjects accrued from mid-1991 to mid-1995. We accrued 5882 cases and 23,517 controls. Increasing NSAID exposure 2-5 years preceding diagnosis was associated with a trend towards a decreasing RR (P-trend = 0.003); for the highest exposure level RR = 0.76, 95% confidence interval 0.63-0.92. This protective effect could not be attributed to confounding by other determinants. In analyses involving only the cases, NSAID exposure 2-5 and 6-10 years preceding diagnosis was associated with significantly reduced risks of presenting with a large tumour (> 5 cm diameter) or distant metastasis, but not regional lymph node metastasis. The use of NSAIDs may retard the growth of breast cancers and prevent distant metastasis.

With the advent of screening and the increased incidence of breast cancer, concern for the prevention of breast cancer has become forefront in today's society. Determining individual risk is the key to prescribing prevention. Prevention of breast cancer is still under clinical investigation with only one drug, tamoxifen, showing benefit in high risk patients. This paper reviews the possible sites for prevention of neoplastic transformation via biomarkers in a breast cell as well as the investigational drugs and their potential use in the chemoprevention of breast cancer.

Recent studies have demonstrated that angiogenesis and suppressed cell-mediated immunity (CMI) play a central role in the pathogenesis of malignant disease facilitating tumour growth, invasion and metastasis. In the majority of tumours, the malignant process is preceded by a pathological condition or exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI. These include: cigarette smoking, chronic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer; chronic viral infections such as human papilloma virus and ano-genital cancers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein-Barr virus (EBV) and lymphomas; chronic inflammatory conditions such as Crohn's disease and ulcerative colitis and colorectal cancer; asbestos exposure and mesothelioma and excessive sunlight exposure/sunburn and malignant melanoma. Chronic exposure to growth factors (insulin-like growth factor-I in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni syndrome) and long-term exposure to immunosuppressive agents (cyclosporin A) may also give rise to similar environments and are associated with the development of a range of solid tumours. The increased blood supply would facilitate the development and proliferation of an abnormal clone or clones of cells arising as the result of: (a) an inherited genetic abnormality; and/or (b) acquired somatic mutations, the latter due to local production and/or enhanced delivery of carcinogens and mutagenic growth factors. With progressive detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process and CMI suppression, thereby facilitating further tumour growth and metastasis. There is accumulating evidence that long-term treatment with cyclo-oxygenase inhibitors (aspirin and indomethacin), cytokines such as interferon-alpha, anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid tumours such as breast and colorectal cancer. These agents are anti-angiogenic and, in the case of aspirin, indomethacin and interferon-alpha have proven immunomodulatory effects. Collectively these observations indicate that angiogenesis and suppressed CMI play a central role in the development and progression of malignant disease.

COX-2-specific inhibitors, by sparing COX-1 enzyme and its physiologic functions, are a safer option than regular NSAIDs in patients who are at risk for gastrointestinal bleeding (e.g., patients with a history of peptic ulcer disease, gastritis, alcoholism, concomitant corticosteroid or anticoagulant use). They have been approved for use in arthritis, and their efficacy is comparable to that of other NSAIDs. Further clinical data are needed to establish the long-term safety profile of these newly introduced drugs.

The development of a COX-2 inhibitor rofecoxib (MK 966, Vioxx) is described. It is essentially equipotent to indomethacin both in vitro and in vivo but without the ulcerogenic side effect due to COX-1 inhibition.